Evaluation of Oxytocin's Efficacy in Reducing Psychosocial Stress Among Breast Cancer Survivors: A Randomized, Placebo-Controlled Clinical Trial

The primary objective of this clinical trial is to evaluate whether the administration of **oxytocin** can induce stress-regulatory effects in breast cancer survivors. This is assessed by measuring the change from baseline in self-reported clinical-behavioral outcomes related to psychological distress. The clinical relevance of this objective lies in the potential for oxytocin to mitigate psychosocial stress, which is a significant concern for breast cancer survivors, potentially improving their overall psychological well-being.

Secondary objectives include assessing changes from baseline after oxytocin administration on:

• Self-reported clinical-behavioral outcomes such as subjective cognitive complaints, quality of life, sleep quality, attachment, and negative thinking.
• Objective cognitive complaints.

• Oxytocin hormonal levels.
• Stress reactivity in daily life through experience sampling and ambulant physiology recording.

The clinical trial focuses on **breast cancer** survivors, specifically targeting a study population of female participants aged between 18 and 65 years. The trial does not include male subjects or vulnerable populations. Participants must have been diagnosed with breast cancer, with or without solitary metastases, excluding solitary brain metastases. They should have completed chemo- and/or radiotherapy between 6 months to 6 years prior to enrollment, although those undergoing prolonged endocrine therapy or immunotherapy are still eligible. Participants are required to have sufficient proficiency in Dutch to complete study tasks. The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize voluntary informed consent and the ability to engage with the study's requirements, ensuring a focus on individuals who can actively participate in the trial's objectives.

The clinical trial is designed to evaluate the **stress-regulatory effects** of **oxytocin** in breast cancer survivors. This study is a randomized, double-blind, placebo-controlled trial, ensuring that neither the participants nor the researchers know who is receiving the active treatment or the placebo, which is a physiological water-based nasal spray containing NaCl 0.9%. The trial is expected to commence on October 1, 2025, and conclude by October 1, 2027, with a total duration of approximately two years. Participants will be involved in the study for a maximum treatment period of five days, with the possibility of early termination if they do not adhere to the study protocol or if any adverse effects are observed.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed. Participants must be between 18 and 65 years old, have a history of breast cancer, and have completed chemo- and/or radiotherapy 6 months to 6 years prior to enrollment. They must also have sufficient proficiency in Dutch. Following the screening, eligible participants will be randomized to receive either the oxytocin nasal spray or the placebo. The primary endpoint is the change from baseline in self-reported psychological distress, measured using the Dutch versions of the Perceived Stress Scale (PSS) and the Depression Anxiety Stress Scale (DASS-42).

Secondary endpoints include assessments from various self-report questionnaires such as the Cognitive Failure Questionnaire (CFQ), Checklist Individual Strength (CIS), and the Quality of Life (WHO-5), among others. Objective cognitive performance will be evaluated using the digital Amsterdam Cognition Scan (ACS). Follow-up visits will be scheduled to monitor the participants' progress and collect data on these endpoints. The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted. Participants may be withdrawn from the study if they experience significant adverse effects or if they choose to withdraw their consent at any point during the trial.

The clinical trial involves the administration of **Oxytocin**, marketed as Oxytocine CD Pharma 40 IE/ml neusspray, oplossing. This experimental medication is formulated as a **nasal spray, solution** and is intended for **intranasal use**. The active substance, oxytocin, is a protein of other origin, and the product is authorized under the marketing authorization number RVG 03716 in the Netherlands by CD Pharmaceuticals AB. The dosage regimen for oxytocin involves a maximum daily dose of 24 IU, with a total maximum dose of 576 IU over a treatment period of up to 5 days. The administration schedule is designed to assess the potential stress-regulatory effects of oxytocin in breast cancer survivors.

The study also includes a **placebo** control, which consists of physiological water-based nasal sprays containing NaCl 0.9%. This placebo is used to provide a baseline for comparison against the effects of the experimental oxytocin treatment. The placebo is administered in the same pharmaceutical form and route as the oxytocin nasal spray, ensuring consistency in the administration process. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy in the clinical trial titled "Assessing Oxytocin's Role in Mitigating Psychosocial Stress in Breast Cancer Survivors" will be evaluated through both primary and secondary endpoints. The primary endpoint focuses on the change from baseline in self-reported clinical-behavioral outcomes of psychological distress following the administration of **oxytocin**. This will be assessed using the Dutch versions of the self-report Perceived Stress Scale (PSS) and the Depression Anxiety Stress Scale (DASS-42).

Secondary endpoints include a range of self-report questionnaires and objective measures. These will involve assessments using the Cognitive Failure Questionnaire (CFQ), Checklist Individual Strength (CIS), Quality of Life (WHO-5), State Adult Attachment Measure (SAAM), Pittsburgh Sleep Quality Index (PSQI), Perseverative Thinking Questionnaire (PTQ), and self-rated impression of severity and improvement (CGI). Additionally, objective cognitive performance will be measured with the digital Amsterdam Cognition Scan (ACS).